An early synthesis of the aforesaid substituted aminoadamantanes, in particular memantine hydrochloride, starting from its precursor 1-bromo-3,5-dimethyladamantane was described in U.S. Pat. No. 3,391,142. This synthesis protocol comprises, in the first step, the reaction between 1-bromo-3,5-dimethyladamantane and large excesses of both acetonitrile and concentrated sulfuric acid, to provide 1-acetamido-3,5-dimethyladamantane by way of the so called Ritter reaction. This reaction, which proceeds via the attack of an acetonitrile on a carbocation that forms in an acid environment followed by formation of an amide, is strongly exothermic, with consequent scale-up problems as the reactors normally used for synthesising pharmaceutical active principles are not designed to dissipate such developed heat. This is because they have in reality to be suitably over-dimensioned in order to be able to handle without serious dangers eventual extreme heat release peaks caused by potential reagent accumulations in the system. In the case of U.S. Pat. No. 3,391,142, also the second synthesis step described therein which leads from the 1-acetamido-3,5-dimethyladamantane to the final product, has shown to be problematic, in that the hydrolysis of 1-acetamido-3,5-dimethyladarnantane is undertaken in the presence of sodium hydroxide in diethylene glycol heated under reflux, i.e. at temperatures exceeding 245° to 250° C. for at least 6 hours, after which the reaction product is poured onto ice. Also these conditions, given the high temperatures needed, not only require special plants, not commonly used in the synthesis of proprietary drugs, but are also very severe—with the consequent danger of impurity formation which then must be removed by often laborious purifications. Specifically referring to U.S. Pat. No. 3,391,142, the free base obtained following the hydrolysis is extracted with benzene, taken up in ether, then added with HCl to provide the addition salt, which is then re-precipitated from a mixture of alcohol and ether.
A more modem synthesis of memantine hydrochloride, this time starting from 1-chloro-3,5-dimethyladamantane, was then described in U.S. Pat. No. 4,122,193. This synthesis protocol involves, in the first step, the reaction between 1-chloro-3,5-dimethyladamantane and urea in a pressure vessel at 220° C. These are also very severe conditions, and, if the reaction is undertaken on an industrial scale, also require special plants and safety arrangements, such as pressure vessels heatable by diathermic oils, normally not used for the synthesis of pharmaceutical active principles. In addition, the conditions described can also lead to in situ degradation of the urea used (whose thermal decomposition under atmospheric conditions takes place already at temperatures greater than 132° C., leading to the formation of biuret, ammonia and hydrocyanic acid), resulting in considerable difficulties in purifying the final product which will have to comply later with the very narrow specifications required for pharmaceutical raw materials.
In addition to the 1-acetamido-3,5-dimethyladamantane known from U.S. Pat. No. 3,391,142, the analogous 1-formamide-3,5-dimethyladamantane could be a hypothetical intermediate on the synthetic route from 1-halogen-3,5-dimethyladamantane to memantine HCl. Indeed, U.S. Pat. No. 5,061,703, in respective examples 6F, 7D, 8E and 9E proposes the synthesis of different N-formyl derivatives of different alkyladamantanes by the reaction between formamide and the respective halogen derivative under formamide reflux conditions. Here also the necessary conditions are very severe and require, for scale-up, considerable plant investment and expedients on an industrial scale. This is because, at atmospheric pressure, formamide boils at 210° C. but according to the data safety sheet its decomposition, to carbon monoxide and ammonia, starts at about 180° C. Indeed, within the sphere of the experiments undertaken by the inventors of the present application, in which 1-halogen-3,5-dimethyladamantane was reacted with formamide under the preferred conditions of U.S. Pat. No. 5,061,703, formation of a dark coloured sublimate was in fact observed on the cooled walls of the reaction container, and the entire reaction mixture appeared, after the prescribed 12 hours under reflux, as a dark pitch which liquefied on heating. And indeed the presence of impurities formed during synthesis of the formamide intermediate continues until the final hydrochloride product is obtained which—if obtained by this path—is less pure.
From the aforegoing, it therefore appears that in the current state of the art there is no synthetic approach free of the aforesaid disadvantages i.e. a synthesis path for aminoadamantanes and their addition salts, in particular memantine HCl, starting from their corresponding halogenated precursors, that can be undertaken on an industrial scale under mild conditions without the need for special equipment—designed either for operating at high temperatures or for dissipating unusual heat development peaks—which provides a final product easily purifiable to purity levels customary for pharmaceutical products and not substantially contaminated with the decomposition products of reagents used upstream. From the above, it also appears that in the current state of the art there is no synthetic approach improved from a safety aspect i.e. that also avoids, in addition to the aforesaid problem of heat development peaks, the development of toxic degradation products such as ammonia, hydrocyanic acid and/or carbon monoxide.
An object of the present invention is therefore the provision of a new synthesis procedure that solves the above mentioned problems.